Heredity (2019) 123:14–17 https://doi.org/10.1038/s41437-019-0191-5

REVIEW ARTICLE

The model organism diaspora

Jonathan Hodgkin1

Received: 23 November 2018 / Accepted: 20 December 2018 © The Genetics Society 2019

The 1950s and 1960s saw an extraordinary flowering of Phycomyces blakesleeanus, described by him as “the most molecular biology and molecular genetics, which revealed intelligent primitive eukaryote” (cited in Fischer and Lipson many of the fundamental secrets of life. After that era, many 1988). Its sporangiophores exhibit an extraordinary range of of the scientists who had contributed to this Golden Age (no sensory abilities, including a still rather mysterious avoid- exaggeration) of discovery looked around for new worlds to ance behaviour whereby the growing sporangiophore is able conquer and new experimental systems to develop. It was to avoid nearby objects (Cerdá-Olmedo 2001). Delbrück obvious that genetic approaches would provide powerful was originally a physicist, and hoped to discover new kinds tools, especially for investigating complex biological phe- of physics by investigating biology, so the unusual avoid- nomena. Francis Crick once accurately remarked, “Genetics ance phenomenon may have piqued his interest. Research 1234567890();,: 1234567890();,: is great for opening up a problem and fantastic in the on Phycomyces was unfortunately hampered by the diffi- endgame, but in the middle you have to do biochemistry”. culties of its sexual system and by inability to achieve For many, it is the first of these phases that is most transformation with exogenous DNA. Delbrück was also rewarding, but it is still crucial to choose the right system avowedly reluctant to get involved with biochemical details for your preferred problems, not least because of the need to (Strauss 2017). do at least some biochemistry. In contrast, Delbrück’s previous choice of an experi- Consequently, in the space of a decade or so, an intel- mental system, the T bacteriophages of Escherichia coli, lectual diaspora of gifted molecular geneticists took place, had been brilliantly successful. He realized in 1939 that as these scientists chose a variety of different organisms for phage provided an ideal route to understanding the funda- their research. Max Delbrück began to work on Phyco- mental nature and properties of genes, as the subsequent myces, Seymour Benzer and David Hogness on Drosophila, history of the “Phage Group” abundantly demonstrated Sydney Brenner on nematodes, Francois Jacob on mice, (Ellis and Delbrück 1939). However, in the longer run T4, George Streisinger on zebrafish, Gunther Stent on leeches, the most popular of these bacteriophages, proved to have a Cyrus Levinthal on Daphnia, Gerry Fink on Arabidopsis, significant defect as an experimental system. The DNA of Bill Dove on Physarum, Dale Kaiser on myxobacteria, Lee T4 is heavily glucosylated, rendering it resistant to most Hartwell and Ron Davis on yeast, and so on. Some of these restriction enzymes and therefore complicating the appli- organisms, such as Drosophila and Arabidopsis, had been cation of many of the techniques of molecular genetics. This studied for decades by conventional genetic methods, but it difficulty could not have been foreseen. Sometimes, unex- was a more open question as to how amenable they might pected problems are there from the outset, one example be to molecular approaches. being Gregor Mendel’s unlucky decision to test the theories Some of these adventures worked out spectacularly well that he had developed by breeding garden peas, by and some did not, for a variety of reasons. One example of experimenting on a different plant. He chose hawkweed, not an interesting organism that never managed to attract a large knowing that these plants reproduce asexually and are also number of researchers was Delbrück’s choice, the fungus highly heterozygous, so his breeding experiments produced incomprehensible results (Nogler 2006). As well as problems, major unforeseen advantages may also become apparent when a new system is being devel- * Jonathan Hodgkin oped, sometimes from the general investment of experi- [email protected] mental effort and sometimes from sheer good fortune. One 1 Department of Biochemistry, University of Oxford, South Parks spectacular early example was the discovery of polytene Road, Oxford OX1 3QU, UK chromosomes in the salivary glands of Drosophila (Painter The model organism diaspora 15

1933), some 20 years after T. H. Morgan had decided on In subsequent decades, other issues became important, fruit-flies as his preferred genetic system. Polytene chro- notably the ability to clone genes, to transform the organ- mosomes added a huge bonus to research on Drosophila, as ism, and eventually to generate physical maps and complete they provided a means of directly visualizing fine details of sequences of the genome. Genome size was and remains an chromosome structure and thereby permitted far more important factor in experimental tractability, from this point sophisticated cytogenetics than was possible in other of view. Both C. elegans and Arabidopsis thaliana were genetic organisms. Polytene chromosomes continued to be found to have very compact genomes (100 and 135 Mb highly advantageous for decades, especially in the era of respectively), which made them significantly more attrac- molecular gene cloning, with the development of in situ tive for genomic approaches. Towards the other end of the hybridization. scale, the zebrafish Danio rerio has a genome of 1400 Mb, However, Nature’s gift of polytene chromosomes did and obtaining a satisfactory complete genome sequence for have one unhelpful consequence, arising from detailed this organism took many years of effort. mutational analyses of defined intervals in the Drosophila The most popular model organisms all had multiple genome, which led to the beguiling “one chromomere, one advantages and thereby lent themselves to many different cistron” hypothesis (Judd et al. 1972). The possibility that kinds of research. In contrast, some organisms have special each visible polytene chromosome band or chromomere properties that rendered them ideal for certain experimental corresponded to an individual gene was exciting and gen- projects, illustrating the principle enunciated by August erated much theorizing as to the nature of the eukaryotic Krogh (Krogh 1929), and before him by Claude Bernard gene. This was a major issue for many years, partly trig- (Bernard 1865). The protist Tetrahymena, for example, gered by the C value paradox: most eukaryote genomes provided a perfect system for the study of telomeres, contain far more DNA than bacterial genomes, suggesting because the generation of its macronucleus entails frag- that eukaryote and prokaryote genes might be different in mentation of its genome into hundreds of minichromosomes some fundamental way. Sadly, the correspondence between and the creation of correspondingly many telomeres. genes and bands in Drosophila evaporated over time, and Another genetically amenable protist, Paramecium, has both ultimately proved to be no more than accidental. interesting behaviour and cells large enough to permit A much later example of good fortune was the discovery microelectrode penetration and electrophysiological of feeding RNA interference (RNAi) in the nematode experiments, thereby permitting the first genetic analyses of Caenorhabditis elegans (Timmons and Fire 1998). This ion channels. species takes up exogenous double-stranded RNA from the Efficient gene cloning and ease of transformation became environment with much greater efficiency than its close major factors in determining the popularity of research relatives, thereby vastly simplifying the application of organisms. Identification and characterization of transpo- whole-genome RNAi screens. Caenorhabditis elegans had sons, as tools for molecular genetics, also became impor- already proved to be a fortunate choice in other ways, for tant. Antirrhinum majus (snapdragon), for example, is not example, in its optical properties and in the ease with which obviously optimal experimental material, but its Tam it can be frozen and stored indefinitely. transposons enabled the ready isolation of floral homeotic So, some model organisms seem to be blessed, others not mutants and the pioneering elucidation of flower morpho- so much. A variety of strategic factors influenced early genesis by Enrico Coen and collaborators (Carpenter and choices in the 1960s, and it was always clear that no single Coen 1990). organism could satisfy all requirements. These factors The question of what genetic system to choose was one included ease and expense of culture, size, complexity, that came up frequently in my own research experiences in transparency, growth rate, generation time, genetic amen- the 1970s. I was fortunate enough to carry out my doctoral ability, long-term storage, behavioural repertoire, natural research at the MRC Laboratory of Molecular Biology variation, background knowledge, phylogenetic position, (LMB) in Cambridge, working on the nematode worm C. scientific community, and medical or economic relevance. elegans under the supervision of Sydney Brenner, some- Some of these factors significantly influenced funding times known as “Father of the Worm” for his role in pio- decisions. Moreover, there were inevitable trade-offs in neering the use of C. elegans. He attracted and inspired experimental advantages, such as those encapsulated in many talented students and postdoctoral scientists who went Quinn’s Law: “The convenience of genetics multiplied by on to found their own research groups and pursue illustrious the quality of the behavioural repertoire is a constant for all careers. Most of these had previous experience in the animals” and Gould’s Corollary: “The quality of the classical systems of molecular genetics (bacteriophage, genetics multiplied by the ease with which single nerve bacteria or fungi), and like their mentors had wondered cells can be identified and penetrated is also a constant” what system to work with next. The worm looked like an (Quinn and Gould 1979). appealing but initially risky possibility. Nevertheless, 16 J. Hodgkin several more senior and established investigators were also months. Among other things, if you are going wrong, you recruited. find out faster. For myself, after 3 years working with C. elegans,I So, short generation times and compact genomes are wanted to try something different and spent a couple of unquestionably convenient from a technical point of view, years at Stanford working in Dale Kaiser’s lab. Dale was but here again there are downsides, for example, in grand one of heroes of research on bacteriophage lambda, which I phylogenetic comparisons and studies of evolution. We found utterly fascinating, but he too had by then (1974) know now that Saccharomyces, Drosophila and C. elegans moved on to something different: myxobacteria, which had have all lost gene families and genetic features that are the advantage of being both multicellular and bacterial important in mammals and were also present in ancestral (Kaiser et al. 1979). But it was also a novel system, and eukaryotes, because they can still be found in the genomes therefore sometimes frustrating. Nevertheless, we made of organisms such as the protist Naegleria gruberi (Fritz- progress. I was tempted to stay at Stanford and continue Laylin et al. 2010) or the cnidarian Nematostella vectensis with Myxococcus xanthus, but Brenner and Crick had (Matus et al. 2007). At least some of these losses probably offered me a research staff position at LMB and it was not arise from the increased number of generations that the fast- clear how long that offer would stay open. Moreover, breeding genetic models have gone through, relative to Brenner said that I could work on anything I liked at LMB, other organisms. short of “studying why the birds sing in the trees”. He may However, this disadvantage was not a consideration in have recalled that my final year undergraduate research the 1970s. At that time, research on C. elegans at LMB and project had involved studying the behaviour of rooks in the elsewhere was expanding rapidly. John Sulston and Bob countryside around Oxford. At the time, I wrote to him that Horvitz had worked out the postembryonic cell lineages of mice looked like ultimately the best system to work on. C. elegans and begun to investigate cell lineage mutants. Nevertheless, starting on mouse genetics would have been Bob Horvitz had also extended some of my own thesis work daunting, despite the hints of new inroads into develop- on meiotic mutants, and we collaborated on a more com- mental biology. Something like the mouse t-complex plete analysis of these. Other parts of my thesis work, on looked important and exciting. However, it was already sex determination and sex-specific developmental mutants, becoming clear that the accumulation of interesting devel- had become more promising and exciting as a result of the opmental mutations in the t-complex was most probably a cell lineage work. Moreover, the “worm breeders” had by sort of genetic artefact, which was a discouraging then grown into a remarkably congenial international realization. research community, thanks in particular to Bob Edgar So the question was, what were the most promising (another T4 veteran, like Horvitz and Brenner himself). The systems, and what really important questions could be easiest and most productive path for me was to drift back attacked productively? What else was out there? Back in into full time research on C. elegans, which is a decision I Cambridge, I spent some time experimenting with Halo- have rarely regretted. bacterium halobium, because Richard Henderson and Nigel In subsequent decades, the proven value of model Unwin had just produced their historic first structure for its organism research has led to yet further choices of plants or purple membrane protein, bacteriorhodopsin (Henderson animals for intensive experimentation—for example, the and Unwin 1975), and Archaea such as Halobacterium moss Physcomitrella patens, the flatworm Schmidtea med- represented virgin territory for bacterial genetics. Unfortu- iterranea, the nematode Pristionchus pacificus and the nately, it became clear that Halobacterium strains were beetle Tribolium castaneum have all acquired substantial appallingly unstable from a genetic point of view, and bodies of information and technical experience. With the therefore going to be hard to work with. An alternative was availability of ever cheaper DNA sequencing, and tools Arabidopsis, which looked tempting. So did Drosophila. such as RNAi and CRISPR/Cas9, it has become possible to However, both the weeds and the flies had generation times contemplate an even wider set of organisms for detailed substantially longer than that of C. elegans, and therefore investigation and manipulation (Goldstein and King 2016). lacked the gratification provided by worms, of getting new A final aspect of these explorations, which have sampled results almost every day. Brenner used to claim that a great variety of organisms, was the broadened attention geneticists chose organisms with generation times propor- paid to the whole panorama of life on earth at a molecular tional to the speed of their own thought processes. This was level. Most of the experimental systems were chosen for scarcely fair to those who worked on maize, which has only their usefulness as general models, but they have also one or two generations a year, yet yielded profoundly provided much valuable information about the special fea- important results in the hands of Emerson, McClintock, tures of their particular taxonomic groups: Drosophila for Rhoades, Beadle and others. However, there is much to be insects, C. elegans for nematodes, Saccharomyces cerevi- said for being able to do genetic crosses in days rather than siae for fungi, and so on. Such information has great and The model organism diaspora 17 continuing relevance to the economic, agricultural and Neupane R, Cipriano M, Mancuso J, Tu H, Salamov A, Lindquist medical applications of basic research, and these practical E, Shapiro H, Lucas S, Grigoriev IV, Cande Z, Fulton C, Rokhsar applications will undoubtedly continue and increase. 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